Vit K

 

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Phytomenadione [Phytonadione] (Lexi-Drugs Multinational) ALERT: US Boxed Warning   Hypersensitivity/anaphylactoid reactions (inj (injection): ection):

Severe reactions, including fatalities, have occurred during and immediately after intravenous (IV) injection of phytonadione, even when precautions have been taken to dilute the phytonadione and to avoid rapid infusion. Severe reactions, including fatalities, also have been reported following intramuscular (IM) administration. Typically Typically,, these severe reactions have resembled hypersensitivity or anaphylaxis, including shock and cardiac or respiratory arrest. Some patients have exhibited these severe reactions on receiving phytonadione for the first time. Therefore, restrict the IV and IM routes to those situations where the subcutaneous route is not feasible and the serious risk involved is considered justified.

Brand Names: International

Bonadiona (CR, DO, GT, HN, NI, PA, SV); Haemokion (AE, BH, CY, EG, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, SY, YE); Hema-K (PH); Kanakion (PT); Kanavit (CZ); Katimin-1 (TW); Kenadion (IN); Konakion (10 mg) (AE, AU, BG, BH, CY, DE, EC, EG, GB, GH, IE, IL, IQ, IR, IT, JO, KE, KW, LB, LY, NL, OM, QA, SA, SE, SY, TZ, UG, YE, ZM); Konakion (BE, DK, ES, HU, IS, LU, NO, SI, TR, ZW); Konakion 10 mg (AT, FI, HN); Konakion MM (BH, CL, HR, KW, LB, LK, LV, MX); Konakion MM Paediatric (BB, BM, BS, BZ, GY, JM, SR, TT); Konakion MM Pediatric (AR, AU, BR, CH, CO, NZ, PE, PK, PY, UY, VN); Neokay (GB); Phytomen (PH); Prohem (ID); Univitan K1 (HK); Vitacon (PL); Vitak (JP); Vitamin K (HK); Vitamin K1 (KR); Vitamine K!1 Roche (FR); Vitka Infant (ID)

Brand Names: US

Mephyton

Brand Names: Canada

 AquaMEPHYTON;; Konakion; Mephyton  AquaMEPHYTON

International Nonproprietary Names (INN)

Fitomenadiona [Spanish]; Phytomenadione [English]; Phytomenadionum [Latin]; Phytoménadione [French]; Фитоменадион [Russian]; ‫دﯾون‬ ‫وﻣﯾﻧ‬ ‫ﻓﯾ‬ [Arabic]

Brazilian Nonproprietary Names (DCB)

Fitomenadiona

Anatomic Therapeutic Chemical (ATC (ATC)) Classification B02BA01

Pharmacologic Category Dosing: Adult

Vitamin, Fat Soluble

Note: Oral route is more effective than the SubQ route in the treatment of nonbleeding patients with warfarin-

associated coagulopathy; SubQ route has therefore fallen out of favor due to erratic and unp unpredictable redictable absorption (Crowther 2002). If  administering parentally, parentally, SubQ is the preferred par parenteral enteral route; IM route should be avoided due to the risk of hematoma formation; IV route should be restricted for emergency use only. only. The American College of Chest Physicians (ACCP) recommends the IV route in patients with major bleeding secondary to use of vitamin K antagonists (VKAs). Adequate intake (AI): Oral: Males: 120 mcg/day; Females: 90 mcg/day Hypoprothrombinemia due to drugs (other than coumarin derivatives) or factors limiting absorption or synthesis:  Oral, SubQ,

IV: Initial: 2.5 to 25 mg (rarely up to 50 mg)  Acute liver failure coagulopathy  coagulopathy : SubQ, IV: 5 to 10 mg (at least one dose) (AASLD [Lee 2011]; Pereira 2005) Vitamin K deficiency (supratherapeutic INR) secondary to VKAs (eg, warfarin) (off-label dose): If INR above therapeutic range to 10 (no evidence of bleeding):

 The,2012 ACCP guidelines recommend administration of oral vitamin K (dose not specified) in this setting (Guyatt 2012). Previously, Previously the 2008 ACCP guidelines recommended to hold warfarin, administer vitamin K orally 2.5 to 5 mg, expect INR to be reduced within 24 to 48 hours, monitor INR more frequently and give additional vitamin K at an appropriate dose if necessary; resume warfarin at an appropriately a ppropriately adjusted dose when INR is in desired range (Hirsh 2008). Others have recommended consideration of vitamin K 2 to 2.5 mg orally or 0.5 to 1 mg IV (Patriquin 2011). http://online.lexi.com/lco/action/doc/retrieve/docid/multinat_f/4669036

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If minor bleeding at any INR elevation: Hold warfarin, may administer vitamin K orally 2.5 to 5 mg, monitor INR more frequently, may

repeat dose after 24 hours if INR correction incomplete; resume warfarin at an appropriately adjusted dose when INR is in desired range (Patriquin 2011). If major bleeding at any INR elevation: The 2012 ACCP guidelines recommend administration of four-factor prothrombin complex

concentrate (PCC) and IV vitamin K 5 to 10 mg in this setting (Guyatt 2012). The only available four-factor PCC in the US is Kcentra. Other four-factor PCCs not available in the US include Beriplex P/N, Cofact, and Octaplex. Bebulin VH and Profilnine SD do not contain adequate levels of factor VII and are considered three-factor PCCs. Previously, the 2008 ACCP guidelines recommended to hold warfarin, administer vitamin K 10 mg by slow IV infusion and supplement with PCC depending on the urgency of the situation; IV vitamin K may be repeated every 12 hours (Hirsh 2008). Note: Use of high doses of vitamin K (eg, 10 to 15 mg) may cause warfarin resistance for ≥1 week. During this period of resistance,

heparin or low-molecular-weight heparin (LMWH) may be given until INR responds (Ansell 2008). Preprocedural/surgical INR normalization in patients receiving warfarin (routine use): Oral: 1 to 2.5 mg once administered on the day before surgery; recheck INR on day of procedure/surgery (Douketis 2012). Others have recommended the use of vitamin K 1 mg orally for mild INR elevations (ie, INR 3.0 to 4.5) (Patriquin 2011). Intracranial hemorrhage associated with vitamin K antagonist anticoagulants (eg, warfarin) (off-label use): IV: Initial: 10 mg once

given as soon as possible and concomitantly with 4-factor prothrombin complex concentrate (PCC) for INR ≥1.4 (3-factor PCC may be given concomitantly with phytonadione but 4-factor PCC is preferred). Subsequent phytonadione administration is guided by follow-up INR; if subsequent INR ≥1.4 within the first 24 to 48 hours after the initial dose, give a repeat dose of phytonadione 10 mg IV (NCS/SCCM [Frontera 2016]). * See Dosage and Administration in AHFS Essentials for additional information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: According to the manufacturer, SubQ is the preferred parenteral route; r oute; IM route should be avoided due

to the risk of hematoma formation; IV route should be restricted for emergency use only. The American College of Chest Physicians (ACCP) recommends the IV route in patients with major bleeding secondary to use of vitamin K antagonists (VKAs).  Adequate intake (AI): Oral: Infants: 0 to 6 months: 2 mcg/day 7 to 12 months: 2.5 mcg/day Children: 1 to 3 years: 30 mcg/day 4 to 8 years: 55 mcg/day 9 to 13 years: 60 mcg/day 14 to 18 years: 75 mcg/day Hemorrhagic disease of the newborn:

Prophylaxis: IM: 0.5 to 1 mg within 1 hour of birth Treatment: IM, SubQ: 1 mg/dose/day; higher doses may be necessary if mother has been receiving oral anticoagulants Vitamin K deficiency (supratherapeutic INR) secondary to vitamin K antagonists (VKAs) (eg, warfarin) (off-label use):  Infants

and Children: Excessively prolonged INR (usually INR >8; no significant bleeding): Note:  Limited data available: IV: 0.03 mg/kg/dose; maximum dose: 1 mg (Bolton-Maggs, 2002); if significant bleeding, consider use of fresh frozen plasma, prothrombin complex concentrates, or recombinant factor VIIa (Monagle, 2012).

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer’s labeling.

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling.

Use: Labeled Indications

Prevention and treatment of hypoprothrombinemia caused by vitamin K antagonist (VKA)-induced (eg, warfarin-induced) or other drug-induced vitamin K deficiency deficiency,, altered activity, or altered metabolism; hypoprothrombinemia caused by malabsorption or inability to synthesize vitamin K; prophylaxis and treatment of hemorrhagic disease of the newborn * See Uses in AHFS Essentials for additional information. http://online.lexi.com/lco/action/doc/retrieve/docid/multinat_f/4669036

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Use: Off-Label   Hypoprothrombinemia d due ue to long-acting anticoagulan anticoagulantt rodenticides (LAARs) Level of Evidence [C]

Data from a few case reports suggest that phytonadione may be beneficial in the treatment of hypoprothrombinemia caused by long-acting anticoagulant rodenticides (brodifacoum) Ref . Data from a limited number of patients (case series) also suggest that phytonadione may be beneficial in this setting phytonadione in the treatment of this condition.

Ref 

. Additional data may be necessary to further define the role of 

  Intracranial hemorrhage associ associated ated with vitamin K antagonist anticoagulants (eg, warfarin) Level of Evidence [G]

Based on the Neurocritical Care Society and the Society of Critical Care Medicine guideline for reversal of antithrombotics in intracranial hemorrhage, phytonadione, with 4-factor prothrombin complex concentrate (PCC), is recommended as soon as possible for vitamin K antagonist-associated intracranial hemorrhage and INR ≥1.4. Three-factor PCC may be given with phytonadione but 4-factor PCC is preferred Ref .

Level of Evidence Definitions   Level of Evidence Scal Scale e A - Consistent evidence from well-performed randomized, controlled trials or overwhelming evidence of some other form (eg,

results of the introduction of penicillin treatment) to support the off-label use. Further research is unlikely to change confidence in the estimate of benefit. B - Evidence from randomized, controlled trials with important limitations (inconsistent results, methodological flaws, indirect

or imprecise), or very strong evidence of some other research design. Further research (if performed) is likely to have an impact on confidence in the estimate of benefit and risk and may change the estimate. C - Evidence from observational studies (eg, retrospective case series/reports providing significant impact on patient care),

unsystematic clinical experience, or from potentially flawed randomized, controlled trials (eg, when limited options exist for condition). Any estimate of effect is uncertain. G - Use has been substantiated by inclusion in at least one evidence-based or consensus-based clinical practice guideline.

Clinical Practice Guidelines Life-Threatening Hemorrhage:

NCS/SCCM, “Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage,” 2016 Stroke:

 AHA/ASA, “Guidelines for the Management of Spontaneous Intracerebral Hemorrhage,” July 2015 Valvular Valvul ar Heart Disease:

 AHA/ACC, “2014 AHA/ACC Guidel Guideline ine for the Management of Pati Patients ents with V Valvular alvular Heart Disease,” March 2014 Other:

 American College of Chest Chest Physicians E Evidence-Based vidence-Based Clinical P Practice ractice Guidelines (9th Edition), Edition), February 2012

Administration: IV

Infuse slowly; rate of infusion should not exceed 1 mg/minute. Alternatively, dilute dose in a minimum of 50 mL of compatible solution and administer using an infusion pump over at least 20 minutes (Ageno, 2012). The injectable route should be used only if the oral route r oute is not feasible or there is a greater urgency to reverse anticoagulation.

Administration: Injectable Detail

pH: 3.5 to 7

Administration: Oral

The parenteral formulation may also be used for small oral doses (eg, 1 mg) or situations in which tablets cannot be swallowed (Crowther 2000; Crowther 2002; O’Connor 1986); may administer undiluted or diluted in a beverage (eg, orange juice) (Vanier 2006).

Storage/Stability Injection: Store at 15°C to 30°C (59°F to 86°F). Protect from light. Note: Store Hospira product at 20°C to 25°C (68°F to 77°F). Oral: Store tablets at 15°C to 30°C (59°F to 86°F). Protect from light.

Preparation for Administration

Dilute injection solution in preservative-free NS, D5W D5W,, or D5NS. To reduce the incidence of anaphylactoid reaction upon IV administration, dilute dose in a minimum of 50 mL of compatible solution and administer using an http://online.lexi.com/lco/action/doc/retrieve/docid/multinat_f/4669036

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infusion pump over at least 20 minutes (Ageno, 2012).

Extemporaneously Prepared  A 1 mg/mL oral suspension suspension may be made with ttablets. ablets. Crush six 5 mg tablets in a mortar  and reduce to a fine powder. Add 5 mL each of water and methylcellulose 1% and mix to a uniform paste. Mix while adding sorbitol in incremental proportions to almost 30 mL; transfer to a calibrated bottle, rinse mortar with sorbitol, and add quantity of sorbitol sufficient to make 30 mL. Label "shake well" and "refrigerate". Stable for 3 days. Nahata MC and Hipple TF, Pediatric Drug Formulations, 3rd ed, Cincinnati, OH: Harvey Whitney Books Co, 1997. Note: The parenteral formulation may also be used for small oral doses (eg, ( eg, 1 mg) or situations in which tablets cannot be swallowed

(Crowther, 2000; O’Connor, O’Connor, 1986); may administer undiluted or diluted in a beverage (eg, ora orange nge juice) (Vanier 2006).

Medication Safety Issues   Sound-alike/look-alike issues:

Mephyton may be confused with melphalan, methadone

Contraindications

Hypersensitivity to phytonadione or any component of the formulation

Warnings/Precautions Concerns related to adverse effects:

• Hypersensitivity/anaphylactoid reactions: [US Boxed Warning]: Severe reactions resembling hypersensitivity reactions (eg, anaphylaxis) have occurred rarely during or immediately after IV administration (even with proper dilution and rate of administration); some patients had no previous exposure to phytonadione. Anaphylactoid reactions typically

occurred when patients received large IV doses administered rapidly with formulations containing polyethoxylated castor oil (also called polyoxyethylated castor oil); proper dosing, dilution, and administration will minimize risk (Ageno 2012; RiegertJohnson 2002). Limit IV administration to situations where an alternative route of administration is not feasible and the benefit of therapy outweighs the risk of hypersensitivity reactions. Allergic reactions have also occurred with IM and SubQ injections, albeit less frequently frequently.. Disease-related concerns:

• Anticoagulant-induced hypoprothrombinemia: In patients receiving a therapeutic vitamin K antagonist (VKA) (eg, warfarin), administer a dose of phytonadione that will quickly lower the INR into a safe range without causing resistance to warfarin. High phytonadione doses may lead to warfarin resistance for at least one week. • Liver disease induced hypoprothrombinemia: If initial doses do not reverse coagulopathy coagulopathy,, then higher doses are unlikely to have any effect. Note: Ineffective in hereditary hypoprothrombinemia. • Long-acting anticoagulant rodenticide (LAAR) ingestion: Patients with LAAR-induced coagulopathy require much larger doses and longer treatment durations (up to months) after exposure compared to that needed to reverse VKA-induced coagulopathy. Special populations:

• Neonates: Use with caution in neonates, especially premature infants; severe hemolytic anemia, jaundice, and hyperbilirubinemia have been reported with larger than recommended doses (10 to 20 mg). Dosage form specific issues:

• Aluminum: The parenteral product may contain aluminum; toxic aluminum concentrations may be seen with high doses, prolonged use, or renal dysfunction. Premature neonates are at higher risk due to immature renal function and aluminum intake from other parenteral sources. Parenteral aluminum exposure of >4 to 5 mcg/kg/day is associated with CNS and bone toxicity; tissue loading may occur at lower doses (Federal Register, 2002). See manufacturer’s labeling. • Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors, 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling. • Polyoxyethylated castor oil: Some injectable dosage forms contain polyoxyethylated castor oil (Cremophor EL) which is associated with hypersensitivity reactions.

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• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivit Hypersensitivity y reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley Shelley,, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling. Other warnings/precautions:

• Appropriate route: Oral administration is the safest and requires the presence of bile salts for absorption. In obstructive jaundice or with biliary fistulas, concurrent administration of bile salts would be necessary for proper absorption. Manufacturers recommend the SubQ route over other parenteral routes, however, SubQ is less predictable when compared to the oral route, and efficacy may be delayed. The American College of Chest Physicians recommends the IV route in patients with major bleeding secondary to use of VKAs such as warfarin. The IV route should be restricted r estricted to emergency situations only where oral phytonadione cannot be used. Efficacy (eg, control of bleeding, decrease in INR) is delayed regardless of route of  administration; patient management may require other treatments in the interim. * See Cautions in AHFS Essentials for additional information.

Geriatric Considerations

No special recommendation for use or dosing in elderly elderly..

Pregnancy Risk Factor: US

C

Pregnancy Considerations  Animal reproduction studies have not been conducted. Phytonadione Phytonadione crosses the placenta placenta in limited concentrations (Kazzi, 1990). The dietary requirements of vitamin K are the same in pregnant and nonpregna nonpregnant nt women (IOM 2000). In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).

Breast-Feeding Considerations

Small amounts of dietary vitamin K can be detected in breast milk and the dietary requirements of vitamin K are the same in nursing and non-nursing women (IOM, 2000). Information following the use of phytonadione has not been located. The manufacturer recommends caution be used if phytonadione is administered to a nursing woman.

Briggs' Drugs in Pregnancy & Lactation Phytonadione

Adverse Reactions Frequency not defined. Cardiovascular: Flushing, hypertension, hypotension Central nervous system: Dizziness Dermatologic: Diaphoresis, erythematous rash, pruritus Gastrointestinal: Dysgeusia, nausea Hypersensitivity:: Anaphylactoid reaction (non-immunologic anaphylaxis), hypersensitivity reaction Hypersensitivity Local: Fibrosis at injection site, injection site reaction Respiratory: Cyanosis, dyspnea * See Cautions in AHFS Essentials for additional information.

Metabolism/Transport Metabolism/T ransport Effects Drug Interactions

None known.

Open Interactions

Mineral Oil: May decrease the serum concentration of Phytonadione. Specifically, mineral oil may decrease the absorption of  phytonadione. Risk C: Monitor therapy  Orlistat: May decrease the serum concentration of Vitamins (Fat Soluble). Management: Administer oral fat soluble vitamins at least 2 hours before or after the administration of orlistat. Similar precautions do not apply to parenterally administered fat soluble vitamins. Risk D: Consider therapy modification

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Vitamin K Antagonists (eg, warfarin): Phytonadione may diminish the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider  therapy modification

Genes of Interest Vitamin K Epoxide Reductase Complex, Subunit 1

Monitoring Parameters

PT PT,, INR; monitor for hypersensitivity reactions if administering IV IV..

Advanced Practitioners Physical Assessment/Monitoring

Note dosing specifics according to use. Assess

degree of bleeding.

Nursing Physical Assessment/Monitoring

Note dosing specifics according to use. Monitor degree of bleeding.

Dosage Forms Considerations Injectable products may contain alcohol, benzyl ben zyl alcohol, polysorbate 80, propylene glycol, or polyoxyethylated/polyethoxylated castor  oil (Cremophor EL).

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product

labeling. Injection, aqueous colloidal: 1 mg/0.5 mL (0.5 mL); 10 mg/mL (1 mL) Injection, aqueous colloidal [preservative free]: 1 mg/0.5 mL (0.5 mL) Tablet, oral: 100 mcg Mephyton®: 5 mg [scored]

Generic Available (US) Pricing: US

Yes

Solution (Phytonadione Injection)

1 mg/0.5 mL (0.5 mL): $21.60 Tablets (Mephyton Oral)

5 mg (100): $7051.21 Disclaimer: The pricing data provide a representative re presentative AWP and/or AAWP AAWP price from a single manufacturer of the bra brand nd and/or 

generic product, respectively. respectively. The pricing data should be used for benchmarking purposes only, and as such should not be used to set or adjudicate any prices for reimbursement or purchasing functions. Pricing data is updated monthly.

Mechanism of Action

Promotes liver synthesis of clotting factors (II, VII, IX, X); however, the exact mechanism as to this

stimulation is unknown. Menadiol is a water soluble form of vitamin K; phytonadione has a more rapid and prolonged effect than menadione; menadiol sodium diphosphate (K4) is half as potent as menadione (K3).

Pharmacodynamics/Kinetics Onset of action: Increased coagulation factors: Oral: 6 to 10 hours; hour s; IV: 1 to 2 hours Peak effect: INR values return to normal: Oral: 24 to 48 hours; IV: 12 to 14 hours  Absorption: Oral: From intestines intestines in presence of bile; SubQ: V Variable; ariable; IM: Readily Metabolism: Rapidly hepatic Excretion: Urine and feces

Local Anesthetic/Vasoconstrictor Precautions Effects on Dental Treatment

No information available to require special precautions

Key adverse event(s) related to dental treatment: Abnormal taste.

Effects on Bleeding

Phytonadione is a synthetic form of vitamin K and has been used as an antidote to reverse warfarininduced bleeding complications or endogenous vitamin K deficiencies.

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Reversal of Oral Anticoagulants

Index Terms

Methylphytyl Napthoquinone; Phylloquinone; Phytomenadione; Vitamin K; Vitamin K1

References  Ageno W, W, Gallus AS, W Wittkowsky ittkowsky A A,, et al, “Oral Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis Thrombosis,, 9th ed:  American College of Chest Chest Physicians E Evidence-Based vidence-Based Clinical P Practice ractice Guidelines,” Chest , 2012, 141(2 Suppl):e44-88.[PubMed 22315269]  Ahlfors CE. Benzyl Benzyl alcohol, kernicterus, and unbound bilirubin. J Pediatr . 2001;139(2):317-319.[PubMed 11487763]  Alade SL, Brown RE, RE, Paquet A Jr. Jr. Polysorbate 80 and E-F E-Ferol erol toxicity toxicity.. Pediatrics. 1986;77(4):593-597.[PubMed 3960626]  Aluminum in large and small volume parenterals used in total parenteral nutrition. Fed Regist . 2002;67(244):77792-77793. To be codified at 21 CFR §201.323.  Andersen P and Godal HC, “Predictable Reduction in Anticoagulant Activity Activity of Warf Warfarin arin by Small Amounts of Vitamin K,” Acta Med  Scand , 1975, 198:269-70.[PubMed 1189983]  Ansell J, Hirsh J, Hylek E, et al, “Pharmacology and Managem Management ent of the Vitamin Vitamin K Antagonists: Am American erican College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition),” Chest , 2008, 133(6 Suppl):160-98.[PubMed 18574265] Bailey B, "Are There Teratogenic Risks Associated With Antidotes Used in the Acute Management of Poisoned Pregnant Women?" Birth Defects Res A Clin Mol Teratol , 2003, 67(2):133-40.[PubMed 12769509] Barash P, P, Kitahata LM, and Mandel S, “Acute Cardiovascular Collapse After Intravenous Phytonadione,” Anesth Analg , 1976, 55(2):304-6.[PubMed 943998] Bolton-Maggs P and Brook L. “The Use of Vitamin K for Reversal of Over-Warfarinization In Children,” Br J Haematol , 2002, 118(3):924.[PubMed 118(3):924.[ PubMed 12181071] Bruno GR, Howland MA, McMeeking A, et al, “Long-Acting Anticoagulant Overdose: Brodifacoum Kinetics and Optimal Vitamin K Dosing,” Ann Emerg Med , 2000, 36(3):262-7.[PubMed 10969235] Centers for Disease Control (CDC). Neonatal deaths associated with use of benzyl alcohol—United States. MMWR Morb Mortal Wkly  Rep. 1982;31(22):290-291. http://www http://www.cdc.gov/mmw .cdc.gov/mmwr/preview/mmwrhtml/00001 r/preview/mmwrhtml/00001109.htm[PubMed 109.htm[PubMed 6810084] Centers for Disease Control (CDC). Unusual syndrome with fatalities among premature infants: association with a new intravenous vitamin E product. MMWR Morb Mortal Wkly Rep. 1984;33(14):198-199. http://www http://www.cdc.gov/mmwr/prev .cdc.gov/mmwr/preview/mmwrhtml/00000319.htm iew/mmwrhtml/00000319.htm.. [PubMed 6423951] Chua JD and Friedenberg WR, “Superwarfarin Poisoning,” Arch Intern Med , 1998, 158(17):1929-32.[PubMed 9759690] Crowther MA, Douketis JD, Schnurr T, et al, "Oral Vitamin K Lowers the International Normalized Ratio More Rapidly Than Subcutaneous Vitamin K in the Treatment of Warfarin-Ass Warfarin-Associated ociated Coagulopathy. A Randomized, Controlled Trial," Ann Intern Med , 2002, 137(4):251-4.[PubMed 12186515] Crowther MA, Julian J, McCarty D, et al, “Treatment of Warfarin-associated Coagulopathy With Oral Vitamin K: A Randomised Controlled Trial”, Lancet , 2000, 356(9241):1551-3.[PubMed 11075768] Douketis JD, Spyropoulos AC, Spencer FA, et al, “Perioperative Management of Antithrombotic Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines,” Chest , 2012, 141(2 Suppl):326-50.[PubMed 22315266] Fiore LD, Scola MA, Cantillon CE, et al, "Anaphylactoid Reactions to Vitamin K," J Thromb Thrombolysis, 2001, 11(2): 175-83. Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al; Guideline for reversal of antithrombotics in intracranial hemorrhage: a statement for  healthcare professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24(1):6-46. [PubMed 26714677] Gunja N, Coggins A, and Bidny S, “Management of Intentional Superwarfarin Poisoning With Long-Term Long-Term Vitamin K and Brodifacoum Levels,” Clin Toxicol , 2011, 49(5):385-90.[PubMed 21740137] Guyatt GH, Akl EA, Crowther M, et al, “Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines,” Chest , 2012, 141(2 Suppl):7-47.[PubMed 22315257] Harrell CC and Kline SS, “Oral Vitamin K1: An Option to Reduce Warfarin's Activity,” Activity,” Ann Pharmacother , 1995, 29(12):1228-32.

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